Building a better understanding of the intracellular tyrosine kinase PTK6 - BRK by BRK

Abstract

Protein tyrosine kinase 6 (PTK6), also referred to as breast tumor kinase BRK, is a member of a distinct family of kinases that is evolutionarily related to the SRC family of tyrosine kinases. While not expressed in the normal mammary gland, PTK6 expression is detected in a large proportion of human mammary gland tumors. In breast tumor cells, PTK6 promotes growth factor signaling and cell migration. PTK6 expression is also increased in a number of other epithelial tumors, including ovarian and colon cancer. In contrast, PTK6 is expressed in diverse normal epithelia, including the linings of the gastrointestinal tract, skin and prostate, where its expression correlates with cell cycle exit and differentiation. Disruption of the mouse Ptk6 gene leads to increased growth and impaired differentiation in the small intestine that is accompanied by increased AKT and Wnt signaling. Following total body irradiation, PTK6 expression is induced in proliferating progenitor cells of the intestine, where it plays an essential role in DNA-damage induced apoptosis. A distinguishing feature of PTK6 is its flexibility in intracellular localization, due to a lack of amino-terminal myristoylation/palmitoylation. Recently a number of substrates of PTK6 have been identified, including nuclear RNA-binding proteins and transcription factors. We discuss PTK6 signaling, its apparent conflicting roles in cancer and normal epithelia, and its potential as a therapeutic target in epithelial cancers.

Fig. 1

Proteins encoded by the PTK6 gene. PTK6 is a 48 kDa protein that consists of Src-homology (SH) 2, SH3, and tyrosine kinase (TK) domains. PTK6 lacks an amino-terminal SH4 domain required for myristoylation/palmitoylation found in the SRC family of tyrosine kinases. The alternatively spliced isoform of PTK6, ALT-PTK6, has a predicted molecular weight of 15 kDa and contains the SH3 domain and a novel proline-rich carboxy terminal sequence (striped area).

Fig. 2

PTK6 activation and downstream signaling. PTK6 is regulated by a variety of factors. Substrates (grey boxes) and interacting proteins may be localized to different cellular compartments (as indicated by double headed arrows). For example, β-catenin has well-established functions at the membrane and in the nucleus, and PTK6 influences β-catenin in both compartments. In most cases the effects that PTK6 has on substrates and binding partners in different cellular compartments merit further exploration. (OPN: osteopontin; HRG: heregulin).